The field of this invention is therapeutic treatment of disease with double stranded nucleic acids which bind transcription factors.
A wide variety of diseases result from the over- or under-expression of one or more genes. Given cells may make insufficient amounts of a protein (e.g. insulin) or too much of a protein, be it a normal protein (e.g. TNF), a mutant protein (e.g. an oncogene), or a non-host protein (e.g. HIV tat). The ultimate goal of therapeutic intervention in such diseases is a selective modulation of gene expression.
A variety of methods of transcriptional modulation in vitro have been reported including the use of anti-sense nucleic acids capable of binding nascent message, intracellular immunization with dominant negative mutants.
With the broad potential therapeutic applications, massive efforts have been extended by prominent laboratories and clinics around the world to extend these methods in vivo. To date, the transcription factor decoy strategy has never been successfully adopted in vivo.
Description of the roles of transcription factors may be found in Nevins, Science 258, 424-429 (1992); Dalton, EMBO J. 11, 11797 (1992); Yee et al. ibid. 6, 2061 (1987), Weintraub et al., Nature 358, 259-261 (1992), Pagano et al., Science 255, 1144-1147 (1992). Viral coat protein-liposome mediated transfection is described by Kaneda et al., Science 243, 375 (1989). Ritzenthaler et al. (1991) Biochem J 280, 157-162; Ritzenthaler et al (1993) J Biol Chem 268, 13625-13631; Bielinska et al., Science 16, 997-1000 (1990) and Sullenger et al., Cell 63, 601-608 (1990) describe inhibition of transcription with double stranded nucleic acids.
A general discussion concerning the mechanism of restenosis may be found in Libby et al., Circulation 86, III-47 (1992) and Clowes et al., J. Cardiovasc. Pharmacol. 14, S12-15 (1989).
The invention provides for the therapeutic treatment of diseases associated with the binding of endogenous transcription factors to genes involved in cell growth, differentiation and signalling or to viral genes. Methods and compositions are provided for blocking the capacity of endogenous trans-activating factors to modulate gene expression and thereby regulating pathological processes including inflammation, intimal hyperplasia, angiogenesis, neoplasia, immune responses and viral infection.
The methods comprise administering to a patient double stranded nucleic acid xe2x80x9cdecoysxe2x80x9d in a form such that the decoys are capable of entering target cells of the patient and specifically binding an endogenous transcription factor, thereby competitively inhibiting the transcription factor from binding to an endogenous gene. The decoys are administered in amounts and under conditions whereby binding of the endogenous transcription factor to the endogenous gene is effectively competitively inhibited without significant host toxicity. Depending on the transcription factor, the methods can effect up- or down-regulation of gene expression. The subject compositions comprise the decoy molecules in a context which provides for pharmacokinetics sufficient for effective therapeutic use.